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Chemokine receptor antagonists and use thereof

a technology of chemokine receptor and antagonist, which is applied in the field of chemokine receptor antagonists, can solve the problems of causing malignant tumors, affecting immune function, and deteriorating gradually in the field of immunological functions,

Inactive Publication Date: 2012-05-01
ONO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compound of the present invention has an antagonistic activity against CXCR4 and is therefore useful as a preventive and / or therapeutic agent for diseased mediated by CXCR4, namely, CXCR4-mediated diseases. Furthermore, the compound of the present invention is also useful as a preventive and / or therapeutic agent for cancerous diseases or infections.

Problems solved by technology

In this process, immunological functions are gradually deteriorated, various immunocompromised states become to develop such as fever, diarrhea and swelling of a lymph node, and various opportunistic infections such as carinii pneumonia are easily complicated.
It is well known that such a state is the onset of AIDS and induces malignant tumors such as Kaposi's sarcoma and becomes severe.

Method used

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  • Chemokine receptor antagonists and use thereof
  • Chemokine receptor antagonists and use thereof
  • Chemokine receptor antagonists and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide

To an acetonitrile (500 mL) solution of 1H-imidazole-2-carboaldehyde (64 g) and triethylamine (140 mL), dimethylsulfamoyl chloride (100 g) was added at room temperature. The reaction solution was stirred at 50° C. for 16 hours. After the reaction solution was cooled to room temperature, the precipitated crystal was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain the crude title compound. The washing was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the crude title compound. The obtained compound was combined with the crystal obtained previously and then washed with ether to obtain the title compound (88.32 g) having the following physical properties.

TLC: Rf 0...

example 2

2,2′-[(benzylimino)bis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

To a 1% acetate-N,N-dimethylformamide (500 mL) solution of the compound (70 g) obtained in Example 1, benzylamine (17.9 mL) was added at 0° C. To the solution, sodium triacetoxyboron (52 g) was added. The reaction solution was stirred at 0° C. for 30 minutes. To the reaction solution, sodium triacetoxyboron (52 g) was added. The reaction solution was heated to room temperature and then stirred at room temperature for 40 hours. The reaction solution was concentrated under reduced pressure. To the residue, an aqueous 5N sodium hydroxide solution was added, thereby adjusting the pH to 12. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. Without purifying the residue, the title compound (79 g) having the followin...

example 3

2,2′-[iminobis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

To an ethanol (350 mL) solution of the compound (55.7 g) obtained in Example 2, 20% palladium hydroxide-carbon (13.6 g) was added under an argon atmosphere. The reaction mixture was stirred under a hydrogen atmosphere at 60° C. for 6 hours. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:10%-saturated aqueous ammonia-methanol=1:0→8:2) to obtain the title compound (28.5 g) having the following physical properties.

TLC: Rf 0.66 (dichrolomethane:methanol:28% aqueous ammonia=80:20:3);

NMR (CDCl3): δ 7.22 (m, 2H), 6.96 (m, 2H), 4.14 (s, 4H), 2.90 (s, 12H).

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PUM

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Abstract

A compound represented by general formula (I):a salt thereof, a solvate thereof, or a prodrug thereof wherein all symbols are as defined in the specification has an antagonistic activity against CXCR4 and is therefore useful as a preventive and / or therapeutic agent for CXCR4-mediated diseases, for example, inflammatory and immune diseases (for example, rheumatoid arthritis, arthritis, systemic erythematosus, retinopathy, macular degeneration, pulmonary fibrosis, transplanted organ rejection, etc.), allergic diseases, infections (for example, human immunodeficiency virus infection, acquired immunodeficiency syndrome, etc.), psychoneurotic diseases, cerebral diseases, cardiac / vascular disease (for example, arteriosclerosis, myocardial infarction, stenocardia, cerebral infarction, chronic arterial occlusive disease, etc.), metabolic diseases, and cancerous diseases (for example, cancer, cancer metastasis, etc.), a preventive and / or therapeutic agent for cancerous diseases or infections, or an agent for regeneration therapy.

Description

TECHNICAL FIELDThe present invention relates to compounds having a basic group which is useful as medicaments, and use thereof.More specifically, the present invention relates to (1) compounds represented by formula (I):(wherein all symbols are as defined hereinafter), and salts thereof, N-oxides thereof or solvates thereof or prodrugs thereof, (2) use thereof, and (3) a method for producing the same.Chemokine is known as a basic protein which has chemotaxis and an activating effect on endogenous leucocytes and also has strong heparin-binding abilities. It is now considered that chemokine is associated with not only control of infiltration of specific leucocytes upon inflammatory and immune responses, but also development, homing of lymphocytes under physiological conditions and migration of hemocyte precursor cells and somatic cells.Differentiation, proliferation and cell death of blood cells are controlled by various cytokines. Inflammation occurs at a local region in a living bod...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D471/10
CPCC07D233/64C07D401/12C07D403/12C07D403/14C07D471/10C07D498/10A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P13/08A61P13/12A61P17/00A61P17/06A61P19/02A61P19/06A61P19/10A61P25/02A61P25/08A61P25/16A61P25/28A61P27/02A61P29/00A61P29/02A61P3/10A61P31/04A61P31/10A61P31/18A61P31/20A61P33/08A61P35/00A61P35/04A61P37/02A61P37/04A61P37/06A61P43/00A61P7/04A61P7/12A61P9/04A61P9/10A61P9/12
Inventor KOKUBO, MASAYAOCHIAI, HIROSHITAKAOKA, YOSHIKAZUSHIBAYAMA, SHIRO
Owner ONO PHARMA CO LTD
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